Manufacture process of organic compounds

ABSTRACT

The present invention relates to a method of preparing N-substituted salicylamides or derivatives thereof, and their salts, hydrates and solvates. In particular, the present invention relates to a method of preparing N-(5-chlorosalicyloyl)-8-aminocaprylic acid (5-CNAC) and its corresponding disodium monohydrate.

This application is a 371 of PCT/EP2005/013454, filed 12/14/2005.

The present invention relates to a method of preparing N-substitutedsalicylamides or derivatives thereof, and their salts, hydrates andsolvates. In particular, the present invention relates to a method ofpreparing N-(5-chlorosalicyloyl)-8-aminocaprylic acid (5-CNAC) and itscorresponding disodium monohydrate.

The N-substituted salicylamides as prepared by the method of the presentinvention are suitable for use in compositions for delivering activeagents via oral or other routes of administration to mammals.

BACKGROUND TO INVENTION

Processes for preparing N-substituted salicylamides are disclosed in,for example, WO00/59863, WO01/92206 and WO01/70219, and an exampleprocess for preparing 5-CNAC (an N-substituted salicylamide) that isknown in the art is shown in Scheme 1.

In addition, a common method of producing the salt of the 5-CNAC in thepresence of NaOH and acetone is as shown in Scheme 2.

The present invention seeks improve the process of the prior art with aview to achieving a robust high yielding process suitable for producingbulk quantities of high quality product.

SUMMARY OF THE INVENTION

In a broad sense, the present invention relates to a method of preparingN-substituted salicylamides or derivatives thereof and their salts. Themethod comprises reacting a chloro-substituted compound of formula (III)(as defined below) with carsalam(6-chloro-2H-1,3-benzoxazine-2,4(3H)-dione) or a derivative thereof, asrequired, in the presence of a source of bromide ions, for example analkali metal bromine salt, e.g. NaBr.

wherein n is and integer from 1 to 8, Q represents a group readilyconvertible to a carboxylic acid moiety and R⁵ and R⁶ are independentlyselected from hydrogen, —OH, NR³R⁴, halogen, C₁, C₂, C₃ or C₄ alkyl, C₁,C₂, C₃ or C₄ alkoxy, C₂, C₃ or C₄ alkenyl where R³ and R⁴ are eachindependently selected from hydrogen, —OH, C₁, C₂, C₃ or C₄ alkyl, C₁,C₂, C₃ or C₄ haloalkyl, C₁, C₂, C₃ or C₄ alkoxy, C₂, C₃ or C₄ alkenyl.

A preferred class of compounds of formula III have the formula III.II asshown below:

The presence of the alkali metal bromine salt (preferably NaBr) isbelieved to allow the formation of the bromo-substituted compound offormula (IIIb)

Furthermore, the aforementioned method of the present invention providesa method of preparing an N-substituted salicylamide of formula (IV) and,by means of, for example, an acid workup, its corresponding freecarboxylic acid (IV.II).

where t is 0, 1, 2, 3, 4, 5 or 6, m is 1, 2, 3 or 4 and R², or wherem>1, each R² independently, is selected from —OH, NR³R⁴, halogen, C₁,C₂, C₃ or C₄ alkyl, C₁, C₂, C₃ or C₄ haloalkyl, C₁, C₂, C₃ or C₄ alkoxy,C₂, C₃ or C₄ alkenyl and R³ and R⁴ are each independently selected fromhydrogen, —OH, C₁, C₂, C₃ or C₄ alkyl, C₁, C₂, C₃ or C₄ haloalkyl, C₁,C₂, C₃ or C₄ alkoxy, C₂, C₃ or C₄ alkenyl.

In another aspect of the Invention, the alkali metal salt (V) of theN-substituted salicylamide is prepared in the presence of an aqueoussolution of the alkali metal cation, M_(a) ⁺, for example Na+, in anacetone/water mixture. Other suitable mixture are any water misciblesolvents, such as acetone/water, ethanol/water or acetonitrile/water.

More specifically, the method of the present invention employs a chlorosubstituted compound of formula (III.II) (as defined below), andespecially a chloro-substituted ester. In particular, the presentinvention relates to a method of preparing(N-(5-chlorosalicyloyl)-8-aminocaprylic acid (5-CNAC) and itscorresponding salts, especially the disodium monohydrate. In a preferredembodiment, the method comprises reacting an alkyl chloro octanoate,especially ethyl chlorooctanoate (ECO), with 6-chloro-carasalam in thepresence of NaBr to form 5-CNAC. The disodium monohydrate salt issubsequently formed by reacting the 5-CNAC with NaOH in an acetone/watermixture.

The N-substituted salicylamides, especially 5-CNAC, as prepared by themethod of the present invention are suitable for use in compositions fordelivering active agents via oral or other routes of administration tomammals. In particular, the compounds prepared for the present inventionmay be used for the delivering of pharmaceutically, physiologically,pharmacologically, radiologically or other active agents to a target inthe body of a warm blooded animal.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

A general reaction sequence according to the invention is shown inScheme 3. In Scheme 3 there is shown a method of preparing N-substitutedsalicylamides or derivatives thereof (IV) and their salts (V) from thecorresponding salicylamide (I), via the corresponding carsalamderivative (II) in the presence of the chloro-substituted compound(III):

In reaction Scheme 3:

t is 0, 1, 2, 3, 4, 5 or 6 and preferably t is 0; p is preferably 0, 1,2, 3, 4, 5, or 6 and preferably p is 1. The hydrates tH₂O and pH₂O shownin Scheme 3 may alternatively be a solvate, a mixed hydrate and solvateor a mixed solvate.

n is and integer from 1 to 8 and preferably n is 6; m is 1, 2, 3 or 4and preferably m is 1.

M is an alkali metal preferably M_(a) is Na or K. Most preferably, thealkali metal M is Na (and therefore M_(a) ⁺ is Na⁺). M may be present inthe form M_(a)Y, where Y is a basic counter-ion, e.g. carbonate orhydroxide. Particularly preferably M_(a)Y is NaOH.

Q represents a group readily convertible to the carboxylic acid moietyof formula (IV.II). For example, Q may represent a protected carboxylicacid group, the protecting group being removeable, preferably in a finalwork-up stage in Step B. Thus Q is a moiety which does not participatein the reaction with the compound of formula (III) in Step B, but issubsequently readily convertible into the free carboxylic acid, such asin acid work-up conditions.

R²— or where m>1, each R² independently—may be selected from —OH, NR³R⁴,halogen, C₁, C₂, C₃ or C₄ alkyl, C₁, C₂, C₃ or C₄ haloalkyl, C₁, C₂, C₃or C₄ alkoxy, C₂, C₃ or C₄ alkenyl.

R³ and R⁴ are each independently selected from hydrogen, —OH, C₁, C₂, C₃or C₄ alkyl, C₁, C₂, C₃ or C₄ haloalkyl, C₁, C₂, C₃ or C₄ alkoxy, C₂, C₃or C₄ alkenyl.

The respective R⁵ and R⁶ moieties are independently selected fromhydrogen, —OH, NR³R⁴, halogen, C₁, C₂, C₃ or C₄ alkyl, C₁, C₂, C₃ or C₄alkoxy, C₂, C₃ or C₄ alkenyl. The respective R⁵ moieties may or may notbe the same and likewise the respective Rr⁵ moieties may be the same ordifferent. Similarly the respective R⁵ and R⁶ moieties may be the sameor different. In a preferred embodiment every R⁵ and every R⁶ ishydrogen.

Halogen may be selected from chloro, fluoro, bromo and iodo. Mostpreferred is chloro.

It is preferred that m is 1 and that R² is halo. Preferably R² ischloro. It is still further preferred that when m is 1, R² is at the5-position.

Step B may comprise one or more sub-steps in which intermediatecompounds are formed but are most preferably not isolated. Suchintermediates may include those identified below as compounds offormulae (IV.I) and (VI).

The present invention may therefore provide an additional step ofsaponifying the reaction mixture containing (IV) to further react theintermediate having the formula (VI) to form the target molecule. Thisstep may be carried out without the need to isolate either of thecompounds of formula IV or VI.

Most preferably the compound of formula (III) is comprises a compound offormula (III.II) below:

in formula (III.II), in general terms, R¹ may be a protecting group forthe carboxy moiety, more especially a group which is substantially inertto reaction with —NH₂ groups during step A but convertible thereafter toa carboxylic acid (—COOH) group. It is especially preferred that R¹ isselected from a linear or branched alkyl group containing 1, 2, 3, 4, 5or 6 carbon atoms, preferably 1, 2, 3 or 4 carbon atoms and particularly1 or 2 carbon atoms, so that formula (III.II) represents an ester. In aparticularly preferred embodiment, R¹ is ethyl (C₂). Thus the compoundof formula (III.II) is most preferably an ester.

A preferred compound of formula (III) and (III.II) is where n is 6 andeach CR⁵R⁶ is CH₂, thus comprising a linear hexyl chain. One preferredcompound comprises ethyl-8-chlorooctanoate (III.II):

A preferred class of compounds formed in the method of the inventionhaving the general formula IV may be exemplified by the formula IV.Ibelow:

where R1 is a protecting group for the carboxy moiety. Such compoundsare preferably intermediates which are not isolated.

In compounds shown herein, such as those of formulae (I) and (IV), whichinclude a phenolic hydroxy group, the said group may be in the form of asalt, for example a sodium salt.

The phenolic hydroxy group may be present in the deprotonated formduring reaction steps A and B, where the presence of a base is required.

Reagents

The following discussion relates to the reagents that are preferablyused in the present invention. Particular reaction conditions arediscussed in a later section.

Step A

In Step A, the salicylamide (I) is converted into the correspondingcarsalam derivative (II) by reaction with an excess of a chloroformatesuch as ethylchloroformate, n-propylchlorformate, i-propylchloroformate,n-butylchloroformate or t-butylchloroformate. Ethylchloroformate isparticularly preferred. The reaction is preferably carried out in atwo-phase system of an alkyl acetate/mild organic base/water. Preferablythe mild organic base is substantially water insoluble.

Examples of an alkyl acetate are methyl acetate, ethyl acetate, n-propylacetate, i-propyl acetate, t-butyl acetate. Most preferably the reactionis carried out in n-butyl acetate.

Examples of a mild organic base are pyridine and a pyridine derivativein particular an alkyl substituted pyridine, for example adialkylsubstituted pyridine, and more especially those pyridinederivatives which are substantially water insoluble. An example of apreferred pyridine derivative is 5-ethyl-2-methyl-pyridine.

Particularly preferably, the reaction is carried out in the two-phasesystem comprising n-butyl acetate/5-ethyl-2-methyl-pyridine/water in anexcess (e.g. 20% excess) of ethylchloroformate. Most preferably, theacetate:water ratio is about 1:1.

Step B

Step B Preferably Comprises a Series of Sub-Steps:

Step B1

Step B1 is the primary reaction step in which the carsalam or carsalamderivative of formula (II) reacts with the chloro-substituted compound(III). Preferably the chloro-substituted compound (III) is an ester andthe reaction is carried out in the presence of a base, such as sodiumcarbonate, and an aprotic solvent such as a dialkylamide, for exampledimethylacetamide or dimethylformamide. Reaction in the presence ofdimethylformamide is preferred. In addition a source of bromide ions,for example a catalytic amount of the alkali metal-bromide MBr, forexample KBr or NaBr, especially NaBr is present.

The aprotic solvents suitable for use in this invention may include, butare not limited to, the following: nitrile compounds (e.g.,acetonitrile, benzonitrile, nitromethane), amide and cyclic amidecompounds (e.g., N,N-dimethylformamide, N-methylformamide,N,N-diethylformamide, N-ethylformamide, N,N-dimethylacetamide,N-methyl-2-pyrrolidone,-hide), ester, cyclic ester, and ether compounds(e.g., tetrahydrofuran, propylene carbonate, ethylene carbonate,gamma-butyrolactone, ethyl acetate, dimethylether), oxide and sulfocompounds (e.g., dimethylsulfoxide, acetone, sulfolane,dimethylsulfone).

Preferably, the aprotic solvent is an amide selected fromN,N-dimethylformamide, N-methylformamide, N,N-diethylformamide,N-ethylformamide, N,N-dimethylacetamide. Most preferably, the solvent isN,N-dimethylformamide.

Step B2

In a second part of step B, an alkali metal salt, for example sodiumhydroxide is added to the reaction mixture together with water.

Step B3

In a third part of step B an acid is added, for example sulfuric acidtogether with an alkyl acetate for example methyl acetate, ethylacetate, n-propyl acetate, i-propyl acetate, t-butyl acetate. Mostpreferably the third part of step B is in the presence of ethyl acetate.Step B3 forms the free acid of formula (IV.II).

Step B4

In a preferred fourth part of Step B, the N-substituted salicylamide(IV.II) is crystallised in an alcohol, for example ethanol/water,however other solvent might be suitable too, especially mixture of ethylacetate, ethanol, water, or acetone/water.

Step C

In step C the N-substituted salicylamide of formula (IV.II) is reactedwith a strong base, for example sodium hydroxide, in the presence ofacetone and water.

The processes of this invention, where carried out in the presence of astrong base, for example, M_(a)Y, may be carried out in the presence ofalkali metal or alkaline earth metal hydroxides, hydrides, amides,alkanolates, phenolates, acetates, carbonates, dialkylamides oralkylsilyl-amides; alkylamines, alkylenediamines, optionallyN-alkylated, optionally unsaturated, cyclo-alkylamines, basicheterocycles, ammonium hydroxides, as well as carbocyclic amines.

Alkyl-alkali metals may be selected from, for example, methyllithium,n-butyllithium, or tertbutyllithium optionally activated withtetramethylethylene diamine (TMEDA).

Alkali metal hydrides, may be selected from, for example, sodium hydrideand calcium hydride.

Alkali metal amides may be selected from, for example, lithium amide orlithium diisopropylamide (LDA), lithium diethylamide, lithiumisopropylcyclohexylamide or potassium bis(trimethylsilyl)amide.

Alkali metal alcoholates or alkali metal alcoholates may be selectedfrom, for example, primary, secondary or tertiary aliphatic alcoholscontaining 1 to 10 carbon atoms, e.g. sodium, potassium or lithiummethylate, sodium, potassium or lithium ethylate, sodium, potassium orlithium n-propylate, sodium potassium or lithium isopropylate, sodium,potassium or lithium n-butylate, sodium, potassium or lithiumsec-butylate, sodium, potassium or lithium tert-butylate, sodiumpotassium or lithium 2-methyl-2-butylate, sodium, potassium or lithium2-methyl-2-pentylate, sodium, potassium or lithium 3-methyl-3-pentylate,sodium potassium or lithium 3-ethyl-3-pentlyate.

Alkaline earth metal phenolates may be selected from, for example,alkaline metal o-alkyl substituted phenolates, alkali metal phenolatesor alkali metal o-alkyl substituted phenolates, e.g. sodium or potassiumo-cresolate.

Amine-based organic bases also may be used and may be selected from, forexample, 2,4,6-Trimethylpyridine;2-tert-Butyl-1,1,3,3-tetramethyl-guanidine;1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU);2,3,4,6,7,8,9,10-Octahydropyrimidol[1,2-a]azepine;1,5-Diazabicyclo[4.3.0]non-5-ene (DBN); diazabicyclooctane (DABCO);1,4-Diazabicyclo(2.2.2)octane (TED); N,N-Dicyclohexylmethylamine;N,N-Diethylaniline; N,N-Diisopropyl-2-ethylbutylamine;N,N-Diisopropylmethylamine; N,N-Diisopropyl-3-pentylamine;N,N-Dimethylaniline; 2,6-Di-tert-butyl-4-methylpyridine;N,N-Diisopropylethylamine; 2,6-Dimethylpyridine;7-Methyl-1,5,7-triazabicyclo(4.4.0)dec-5-ene (MTBD);3,3,6,9,9-Pentamethyl-2,10-diazabicyclo-(4.4.0)dec-1-ene (PMDBD);1,2,2,6,6-Pentamethylpiperidine (PMP); Triethylamine;1,1,3,3-Tetramethylguanidine (TMG);N,N,N′,N′-Tetramethyl-1,8-naphthalenediamine;2,2,6,6-Tetramethylpiperidine (TMP);1,5,7-Triazabicyclo(4.4.0)dec-5-ene,1,3,4,6,7,8-Hexahydro-2H-pyrimido[1,2-a]pyrimidine (TBD); Tributylamine;2,4,6-Tri-tert-butylpyridine; Tris(trimethylsilyl)amine; andalkyl-ammonium hydroxides.

However, a mixture of the above bases may also be employed.

Those which may be mentioned by way of example are sodium hydroxide,hydride, amide, methanolate, acetate, carbonate, potassiumtert.-butanolate, hydroxide, carbonate, hydride, lithiumdiisopropylamide, potassium bis(trimethylsilyl)-amide, calcium hydride,triethylamine, diisopropylethylamine, triethylenediamine,cyclohexylamine, N-cyclohexyl-N,N-dimethyl-amine, N,N-diethylaniline,pyridine, 4-(N,N-dimethylamino)pyridine, quinuclidine,N-methyl-morpholine, benzyltrimethylammonium, as well as1,5-diazabicyclo[5.4.0]undec-5-ene (DBU).

In the processes of this invention the preferred bases are alkali metalhydroxides and carbonates, for example sodium hydroxide and sodiumcarbonate.

In preferred reaction conditions of step C, the acetone:water ratio isabout 3:1, which may be increased up to 4:1, or even about 5:1 up to ahighest level of about 15:1, during the reaction by addition of furtheracetone to the reaction mixture.

It will be understood that in between addition of reagents and inparticularly in between steps A, B or C, or indeed between the variousparts of step B, evaporation, filtration, extraction and other finaland/or preparatory steps may be conducted prior to commencing the nextstep.

Conditions

Unless stated to the contrary, the reaction steps of the presentinvention are most preferably conducted in an inert atmosphere, forexample under a nitrogen atmosphere.

Step A

In step A, the reaction mixture is cooled to 0-5° C. during the additionof the chloroformate and the mixture is then slowly heated to refluxtemperature and refluxed until the reaction has reached a sufficientdegree of completion. Typically the reaction mixture is refluxed forabout 3 to 7 hours, and more especially for about 5 hours. Thetemperature of the reflux is dependent upon the alkyl acetate solventpresent. A typical reflux temperature is in the range of 80 to 120° C.

Step B

In step B1, after addition of all the components of the reaction mixtureexcept the sodium carbonate, the reaction mixture is heated to about100° C. The addition of sodium carbonate then preferably takes placeover about two hours.

In step B2, the reaction mixture of is heated to about 100° C.

In step B3, the reaction mixture is cooled to about 60° C. prior to theaddition of the acid. Preferably a temperature of about 60° C. ismaintained throughout the reaction and this temperature is preferablymaintained throughout any subsequent purification steps, for exampleextractions.

In step B4, the alcohol (preferably ethanol) is added at about 50-60° C.and then the solution cooled to about 40-50° C. Finally, the solution iscooled to about 0-5° C.

In preferred embodiments, the present invention relates to a method ofpreparing N-(5-chlorosalicyloyl)-8-aminocaprylic acid (5-CNAC) and itscorresponding salts, in particular its disodium monohydrate. In oneparticularly preferred embodiment, 5-CNAC is prepared from5-chlorosalicyclic acid via 5-chloro carsalam, in the presence ofethyl-8 chlorooctanoate (ECO) as shown in Scheme 4 below:

The reagents for steps A, B and C are as hereinbefore described inScheme 3.

The most preferred reagents for processes described in the presentinvention, in particular for the process of Scheme 4 are as follows:

In step A, the 5-chloro-salicylamide is reacted with ethylchloroformate(excess) in an n-butyl acetate/water mixture, with5-ethyl-2-methyl-pyridine acting as the required organic base.

In step B1 the 5-chloro-carsalam is reacted with ethylchlorooctanoate inthe presence of a sodium carbonate and NaBr (bromide ion source) indimethylformamide. NaBr is believed to act catalytically. In step B2,the resulting product is treated with, for example aqueous sodiumhydroxide. Then, an acid, preferably a mineral acid such as sulfuricacid, is added followed by ethyl acetate. The crude product isrecrystallised in ethanol.

In step C the 5-CNAC is treated with sodium hydroxide in anacetone/water mixture, preferably at a ratio of acetone:water of 3:1.

A second aspect of the present invention, relates to the use of theN-substituted salicylamides and derivatives thereof, in particular5-CNAC, and their corresponding salts, in particular their disodiummonohydrate salts, when prepared by the method of the present invention,for delivering active agents, such as biologically or chemically activeagents, to a target.

A third aspect of the present invention relates to pharmaceuticalcompositions of the N-substituted salicylamides and derivatives thereofand salts thereof when prepared by the method of the present invention.In particular the present invention relates to pharmaceuticalcompositions comprising 5-CNAC when the 5-CNAC is prepared by the methodof the present invention

The disclosure hereinafter discusses the merits of the present inventionprimarily in terms of the synthesis of 5-CNAC. However, it will beappreciated that the discussion of the invention in these terms is notintended to limit the scope of the invention, which extends to theN-substituted salicylamides of general formula IV. Thus the followingdiscussion of the synthesis in terms of 5-CNAC merely represents apreferred embodiment of the present invention which conveniently allowsfor comparisons between the present invention and the prior art. Theskilled man will appreciate that the process of the present invention isnot limited only to the synthesis of 5-CNAC.

A preferred synthesis of the present invention provides an improvedprocedure for obtaining 5-CNAC as compared to the prior art. It will berecalled that the prior art, as described in Scheme 1, is a process inwhich the formation of 5-CNAC is achieved by reaction with ethyl-8bromooctanoate in the presence of sodium carbonate anddimethylacetamide.

The synthesis of 5-CNAC of the present invention advantageously uses5-chlorosalicylamide as a newly available starting material instead of5-chlorosalicylic acid in the prior art, thus avoiding currently presentin the prior art.

The present invention also provides a new procedure for the synthesis of6-chlorocarsalam, a key intermediate in the process for the manufactureof 5-CNAC, in which a two-phase mixture (for example n-butylacetate/water) with an alkyl substituted pyridine, for example adialkylsubstituted pyridine such as 5-ethyl-2-methyl-pyridine as thebase is used. The use of pyridine as the mild organic base is notprecluded in the present invention, although it is not preferred. Oneparticular advantage of using certain pyridine derivatives, e.g.5-ethyl-2-methyl-pyridine, instead of pyridine in the prior art is thatthe former is recoverable under these conditions. In comparison, theprior art process uses a reaction mixture consisting ofethylchloroformate in acetonitrile, with pyridine as the base, nonebeing reported as recoverable.

The process of the present invention also achieves a major advantageover the prior art by the use of the two-phase system. This systemenables the hydrolysis of unwanted intermediates caused by sidereactions, which in turn removes them from the reaction mixture and as aresult provides a much purer final product.

In a preferred synthesis of 5-CNAC from the previously prepared6-chlorocarsalam according to the method of the present invention,ethyl-8-chlorooctonoate (ECO) is reacted with 6-chloro-carsalam in thepresence of dimethylformamide and sodium carbonate (acting as the base)together with an amount of sodium bromide. These conditions are believedby the inventors to allow the formation of the more reactiveethyl-8-bromooctonoate (EBO) In situ. Sodium bromide can be recovered atthe end of the reaction and in at least this sense the sodium bromide isbelieved to act catalytically. Therefore the process of the presentinvention has removed the need to use ethyl-8-bromooctonoate (EBO)directly as a starting material. EBO has known health and environmentalconcerns due to its highly reactive characteristics. Furthermore, ECO ischeaper and more readily available than EBO.

The intermediate ester (or esters) formed by the aforementioned reactionis (are) most preferably not isolated but saponified immediately afterconcentration of the end reaction mixture. This saponification isadvantageous in eliminating the necessity of isolation of the product,thereby increasing the likelihood of obtaining a higher yield. This canbe contrasted with the corresponding stage of the prior art whichrequired the isolation of8-[6-chloro-2H-1,3-benzoxazine-2,4(3H)dionyl]octanoate. The highly purefree acid is then obtained by extraction and crystallisation.

Finally, the formation of the disodium monohydrate is formed (Step C) bythe addition of sodium hydroxide in an acetone/water mixtureadvantageously allows a crystallisation from a homogenous solution, incontrast to the emulsion of the prior art where sodium hydroxide isadded to pure acetone. The homogeneous solution allows large crystals tobe obtained which might be dried on a standard rotary paddle.

As a result of the changes implemented by the present invention (asexemplified for the above process for the synthesis of 5-CNAC), a newprocess has been developed that provides N-substituted salicylamides offormula IV, especially 5-CNAC (IVA), in both a cost-effective manner andat high purity.

The process of the present invention, using the synthesis of 5-CNAC asan example, is described below in further detail, with particularreference to Schemes 5 and 6 below:

Step A

The temperature T as illustrated in Scheme 5 is preferably in the rangeof 80-120° C. Most preferably the temperature T is between 85-95° C.Particularly preferably, the temperature T is 90° C.

A notable weakness of the prior art process is that it mainly gives aproduct which contains up to 10% of the starting amide (IA). A secondweakness is that the process is run in acetonitrile and pyridine (as canbe seen from Scheme 1), where both acetonitrile and pyridine areunsuitable for recycling. This is both commercially more costly andenvironmentally less desirable.

The corresponding step of the prior art process has two parts:

(i) acylation with ethylchloroformate at 0° C. and

(ii) ring closure at reflux (90° C.).

HPLC analysis of the products of the prior art process has shown thatduring the acylation mainly one intermediate is formed while thestarting material disappears completely. Upon heating, however, asecond, new, Intermediate is formed quickly, which slowly goes over tothe desired 6-Cl-carsalam, together with some starting material. Thefirst intermediate is the N-acylated salicylamide (X), and the second isthe O-acylated derivative (XX) (via the phenolic OH).

In order to overcome the environmental problems associated with theprior art process, the inventors of the present invention first lookedat an aqueous system, using a base such as sodium hydroxide instead ofpyridine. However, it was found that when running the reaction in anaqueous medium with, for example, sodium hydroxide or sodium carbonateinstead of pyridine, after ring closure and the formation of compoundIIA, much more starting material IA was present than in the prior artprocess suggesting that the reaction had not gone to completion or thatdecomposition had occurred.

It was hypothesized that a further intermediate product is thereforeformed, which upon heating may revert back to the starting material.This could be the O-acylated amide, which is not separated by HPLC. Thismay be consistent with an increased reactivity at the amide-oxygen atom,as it is usually the case with strong bases, which favour O-acylation.

Another explanation could be the decomposition of 6-chlorcarsalam underbasic conditions in the same manner as occurs in Step B (ring openingwith sodium carbonate at elevated temperature in dimethylformamide).However this explanation does not apply with pyridine. It was apparent,therefore, that mild organic bases were much to be preferred.

In order to overcome the aforementioned “incomplete” reaction problem,the present invention provides a two-phase system. A preferred system isalkylacetate/organic base/water, for examplebutylacetate/substituted-pyridine/water, with an excessethylchloroformate. Most preferred is n-butyl acetate/5-ethyl-2-methylpyridine/water.

It is hypothesized that in presence of water, hydrolysis of any unwantedintermediates (for example the O-acylated intermediate) occurs rapidly,allowing acylation at the desired N atom (an amide nitrogen) so long asthere is enough chloroformate. Under these conditions (20% excessethylchlorformate and 30% alkyl-substituted pyridine) only 1-2% startingmaterial is found after ring closure.

Since pyridine is not easily recovered from the aqueous mother liquorsit is preferably replaced, without loss of selectivity, with a non-watersoluble pyridine derivative, especially an alkyl pyridine, for examplethe non-water soluble 5-ethyl-2-methyl-pyridine. The use of a non-watersoluble alkyl-pyridine allows the base to be recovered and so ispreferred.

The organic acetate solvent may be selected from methyl acetate, ethylacetate, n-propyl acetate, isopropyl acetate or n-butylacetate. Thepreferred solvent is n-butylacetate, which azeotrope boils at about 90°C. This allows a fast reaction typically of about 4-5 h at reflux. Thereaction in other solvents, such as ethyl acetate or isopropyl acetatealthough successful, requires more time since the boiling points ofthese solvents are lower.

Butylacetate is further preferred due to its low aqueous solubilitycharacteristics. Since butylacetate is substantially insoluble withwater, it keeps IA in solution, thus yielding a very pure product(higher than 98%). This is purer than the prior art process in which aless pure product of a mixture of IA/IIA is given. The yield of thereaction is over 90%, which is similar to the prior art process, exceptthat the higher purity of the present process means that the overallyield of the product IIA is higher for the present invention.

During ring closure, the mixture is preferably slowly (within two hours)heated from 0° C. through to about 90° C. and refluxed.

It is noted that in the process of the present invention, noover-alkylated carsalam (which could be formed when IIA reacts withethylchloroformate) was observed, thus showing that excess reagent isdestroyed before ring closure occurs, which is beneficial.

IIA is readily purified by refluxing it in ethyl acetate/water allowingremoval of up to 10% starting material without loss of yield, shouldthis be necessary.

By-Products of Step A

The corresponding 3,5-dichloro-isomer may be present in the startingmaterial IA, leading to the 3,5-dichloro-isomer by-product. Preferablyless than 1% and in particular less than 0.5% of the 3,5-dichloro-isomeris present in either the starting material or the final product, morepreferably less than 0.07%

Step B

Reference is made in particular to Scheme 6 below:

The compound ethyl-8-bromo-octanoate (EBO), which is used in the priorart processes comes at a high cost, both financially and environmentallysince not only is it relatively expensive to buy but also, due to itshigh reactivity, It is a potential mutagenic alkylating agent and socauses serious safety issues both for its use and its disposal. On theother hand, the chloro equivalent, ECO, is cheaper and, due to its lowerreactivity, is less of an environmental problem and health hazard. Thehealth, economic and environmental advantages of ECO therefore enhancethe benefits of the process of the present invention.

In the development of the process of the invention, the change from EBOto ECO initially posed significant problems during thisalkylation/deprotection step, which results in the free acid (IV.II) or(IVA). These problems were however identified and overcome, as will beseen below, to establish the method of the present invention.

It was found that compared to prior art, alkylation with only ECOpresent was slow at 80° C., presumably due to the lower reactivity ofthe chlorine-reagent. Further, with prolonged reaction time (required toensure completion) more side products were formed. For example, underthe same conditions 0.1% di-acid by-product was formed with EBO, and 7%with ECO.

Increasing the temperature to 100° C. increased the rate of the reactionbut also increased the rate of decomposition of the “carsalam” salt. Infact in presence of moisture, sodium carbonate does not give cleanly thecarsalam-sodium salt, it also opens partially the ring, producing thecorresponding amide (IA) which reacts at both positions O and N. Thedi-alkylated by-product which is thereby formed is not easily removed inthe final step and therefore contaminates the final product. Formationof the di-alkylayed product is therefore not desirable.

From experiments it was noted that only 2.2% di-acid byproduct wasgenerated with 1 eq. NaBr at 80° C. in comparison to 7% without NaBr.

Under the preferred, optimized, conditions of 1 equivalents ECO, 0.2equivalents sodium bromide, 0.55 equivalents sodium carbonate, at 100°C., the alkylation proceeds with 95% selectivity accompanied by onlyabout 2% di-alkylation, less than 1% O-alkylation and full consumptionof ECO.

Finally, in order to prevent degradation of (IIA), in the laboratoryscale synthesis, the base (typically sodium carbonate) and IIA arepreferably first mixed together in an aprotic solvent (preferablydimethylormamide), and heated to 100° C. prior to a slow addition of(III.III). With exemplary amounts being 0.98 equivalents of (III.III),0.6 equivalents base (typically sodium carbonate) and 0.1 equivalents ofsodium bromide, the present invention provides, reproducibly, analkylation with about 95% desired product (mixture of ring closed andopened ester), about 2% di-alkylated ester and about 3% remaining (IIA).

It was found that, where sodium carbonate is used as the base, mixingall the starting materials together at room temperature followed byheating at a given rate led to the uncontrolled release of CO₂, togetherwith a transient thickness of the slurry, which is not convenient.

Therefore, in an enhanced synthesis, all of the starting materialsexcept sodium carbonate are mixed together. The resulting mixture isthen heated up to 100° C. and only then is the sodium carbonated slowlyadded, preferably portion-wise, or continuously in the solid form. Noreaction occurs without sodium carbonate. The sole parameters to controlare the amount and rate of base (sodium carbonate) addition.

For this alternative variation of the synthesis of the presentinvention, a slight excess of sodium carbonate is preferred (0.55equivalents which corresponds to 1.05-1.1 equivalents base) andpreferably the sodium carbonate is added over about 2 hours. This givesa reaction with only a minor side reaction (less than 1% di-alkylation).In order to obtain more than 95% selectivity (i.e. 95% of the desiredconversion), 1 equivalents of (III.III) (instead of 0.98) and 0.2equivalents sodium bromide (instead of 0.1 equivalents) areadvantageously used.

Ring opening occurs by the end of the reaction of step B1, although thistends not to be complete and is believed to be dependent on the amountof excess of sodium carbonate used. Typically at least 30-50% ringopening occurs by the end of the reaction step, making the isolation ofthe pure intermediate (VIA) undesirable. Advantageously, however,saponification and completion of the ring opening are then carried outimmediately in the same vessel since after saponification bothintermediates (VIA and VIIA) give the desired product, IVA. Thereby onesingle product IVA (5-CNAC free acid) is obtained, which can be isolatedafter acidification.

To optimise the saponification, so avoiding isolation of theintermediate, preferably the solvent should be eliminated totally bydistillation. In order to do this, it is preferred to usedimethylformamide instead of dimethylacetamide, since DMF has a lowerboiling point.

The solvent is removed by distillation under vacuum at 100° C., leavingan oily heterogeneous residue. The latter was mixed with water andtreated at 80-100° C. with excess sodium hydroxide. Ring opening andsaponification are very rapid. After saponification, the solution wascooled to 60° C., neutralized with sulfuric acid to pH 8-9 andafterwards diluted with ethylacetate.

Thereafter, the pH was lowered to 2-3, allowing the product to go intothe organic phase. The water phase is discarded and the organic phase iswashed with water. Then fresh water was added and the ethylacetatedistilled off under normal pressure, leaving IVA as a suspension inwater. At that stage, or even before, isolation of the crude product ispossible.

The aqueous suspension was diluted with ethanol, which allowed thedissolution of the acid (IVA) at around 60° C. To this solution is addedan amount of sodium hydroxide, which was revealed to be necessary tokeep the di-acid by-product in the solution (and thus not contaminatethe crystallisation process). Upon cooling pure IVA crystallizes out ofthe solution. It is collected by centrifugation at 0° C. and dried undervacuum at 60° C. Preferably, the di-acid is present below 0.6%.

The above crystallization of IVA is optimized in such a way to removethe by-products (mainly remaining starting material, di-acid and in somecases the dimer). Preferably the final product, IVA, is greater than 99%pure with less than 0.2% of the dimer present.

By-Products of Step B

(III.III) (ethyl-8-chlorooctanoate).

Preferably, the ethyl-8-chlorooctanoate does not contain anydichlorohexane. It has been shown that in a sample containing up to 1%dichlorohexane plus other by-product, the dichlorohexane reacts with IIAto form a dimeric by-product, which is, as has be mentioned before,extremely difficult to separate out form the final acid product (IVA).Particularly preferably, ethyl-8-chlorooctanoate at >99% purity withless than 0.1% dichlorohexane is used.

Where sodium carbonate is used it must be highly pure since impurecompound can lead to incomplete reaction, extended ring opening andexcessive di-alkylated by-product formation.

A possible by-product is the 5-CNAC ethylester, which may be formed dueto incomplete saponification or formed by esterification of the freeacid during the end crystallization from ethanol/water.

Further, as indicated earlier, there may be residual IA, thecorresponding 5-chlorosalicylic acid and the so-called “dimer” if morethen 0.1% dichlorhexane is present in (III.III).

With 0.1% dichlorohexane in (III.III) it is predicted that the dimercontamination could be about 0.3% in IVA and below 0.1% in (VA).

In order to further purify (IVA), if required, an additional extractionwith butylacetate after the saponification and partial neutralizationmay be conducted. At that stage, at pH 8-9. IVA is still water soluble(as its mono sodium salt) whereas the dimer, which cannot make a salt atthis pH (no carboxylic acid), may be extracted. The main drawback ofthis modification is that a large amount of butylacetate is necessary toobtain a phase separation.

Other potential impurities like chlorine isomers in the aromatic ringand C7, C8 homologues of the alkyl chain may theoretically be present insmall quantities (less than 0.05%) but preferably are already excludeddue to their control in the starting materials.

In order to keep by-products to the minimum, it is preferred that, inparticular, the following parameters are regulated, as hereinbeforedescribed:

-   -   Quality and amounts of starting materials: (IIA), (III.III),        base (such as sodium carbonate), bromine salt (such as sodium        bromide).    -   Temperature of the reaction mixture and rate of sodium carbonate        addition.    -   Distillation of the aprotic solvent (such as DMF), and amount of        strong base (e.g. sodium hydroxide) (saponification).    -   Ratio ethanol/water and amount sodium hydroxide during        crystallization.

Furthermore, the quality and relative amounts of starting materials areimportant for the quality of (IVA). Too much (III.III) and sodiumcarbonate (or too little IIA) is likely to have a direct impact on theamount of di-alkylated by-product formed, which to a certain extent isremoved on the crystallization and potential rework. However a drop inthe yield may also play a role in the formation of by-products, forexample for about 20% less yield 10% over alkylation has been observed.

The present invention has therefore revised and improved the process ofthe prior art, and provided a “one pot” process to enable an increasethe yield by as much as 20 percentage points (about 84% versus 64%) withequal or better purity.

Step C

The prior art crystallization techniques had the followingdisadvantages: Crystallization occurred under reflux from an emulsion(after addition of concentrated sodium hydroxide to 5-CNAC free acid inacetone) without seeding. Therefore, no control of the crystallizationwas possible, although it might be that a certain thermodynamicequilibrium is obtained under these crystallization conditions,preventing such a control.

The present invention has provided a crystallisation technique in whichthe N-substituted salicylcamide (IV, IV.II and IVA) crystallises in anacetone/water mixture in the presence of an alkali metal base,especially sodium hydroxide. Independent from the reaction conditions, apolyhydrate, for example a hexahydrate, of IV, IV.II or IVA crystallizesfirst in the acetone/water mix, which then forms the monohydrate V or VAupon drying. Usually the wet cake contains about 12% water which isconsistent with 2-3 molecules of water per 5-CNAC molecule.

Crystallization with only one equivalent water may be achieved usingsodium methylate. This may give a solvate which corresponds to adifferent crystal modification.

Step C is itself inventive. In the preferred method steps, compound(IV.II or IVA), acetone and water are combined. The acetone:water ratiomay be from about 5:1 v/v to about 15:1 v/v, e.g. about 10:1 to 11:1. Abase is added to the mixture suitably at a slightly elevatedtemperature, e.g. about 40° C. to 60° C., for example 45° C. to 55° C.Further acetone may be added, for example as an acetone/water mixture,(e.g. from 2:1 v/v to 4:1 v/v, such as 3:1 v/v), suitably keeping thetemperature at a moderately elevated level (e.g. 45° C.-55° C.). Thesalt is then isolated. One procedure is as follows: if the temperatureis above 50° C., it is reduced to 50° C. or less (e.g. 40° C. to 50° C.such as 45° C. to 48° C.) and seed crystals are added to inducecrystallisation, before further reducing the temperature (e.g. to 0° C.to 5° C.) to finish the crystallisation step prior to isolating thecrystals. Stirring is suitably continued throughout. The crystals may bedried under vacuum 50-60 mbar at 50-55° C. for at least 24 hours.

It was observed that crystallization and stirring which occurred athigher temperatures (40-50° C.), afforded larger crystals (up to 500micron). Further, crystallisation at about 0° C. provides differentcrystal types to those at higher temperatures.

In an alternative crystallisation process, the crystallisation isconducted from 2-pentanone at 80° C.

Preferably, crystallisation occurs, with seeding, at 45-50° C., followedby the addition of more acetone at the same temperature, then cooling to0° C. to give the desired polymorph. A particularly favourable polymorphis obtained by prolonged stirring over 24 h at 0° C.

The resulting salt, V or VA is preferably >99% pure, without anyby-product over 0.1%.

The theoretical amount of water in VA should be 4.8% calculated for amonohydrate. In fact the water content depends of the conditions andduration of drying. At 80-100-mbar pressure and 40-55° C. no over-dryingoccurs. However to avoid any risk it is recommended to check the watercontent during the drying process. Further, it appeared in some casesthat the residual amount of acetone after drying was over theestablished limit of 0.5%.

In order to keep by-products to the minimum, it is preferred that, inparticular, the following parameters are regulated, as hereinbeforedescribed:

-   -   The amount and quality of the alkali metal base (sodium        hydroxide)    -   The temperature of seeding and crystallization    -   The rate of saturation    -   The rate of cooling    -   The time of agitation at 0° C.    -   The drying procedure.

Throughout the description and claims of this specification, the words“comprise” and “contain” and variations of the words, for example“comprising” and “comprises”, means “including but not limited to”, andis not intended to (and does not) exclude other moieties, additives,components, integers or steps.

In the processes of the present invention, it is contemplated thatwherever desired, one or more protecting groups may be present in thecompounds for one or more of the functional groups that are not toparticipate in a particular reaction or reaction step or stage, or thatwould interfere with the reaction.

The protection of functional groups by such protecting groups, suitablereagents for their introduction, suitable protecting groups andreactions for their removal will be familiar to the person skilled inthe art. Examples of suitable protecting groups can be found in standardworks, such as J. F. W. McOmie, “Protective Groups in OrganicChemistry”, Plenum Press, London and New York 1973, in T. W. Greene andP. G. M. Wuts, “Protective Groups in Organic Synthesis”, Third edition,Wiley, New York 1999, in “The Peptides”; Volume 3 (editors: E. Gross andJ. Meienhofer), Academic Press, London and New York 1981, in “Methodender organischen Chemie”, Houben-Weyl, 4th edition, Vol. 15/I, GeorgThieme Verlag, Stuttgart 1974, in H.-D. Jakubke and H. Jescheit,“Aminosauren, Peptide, Proteine”, Verlag Chemie, Weinheim, DeerfieldBeach, and Basel 1982, and/or in Jochen Lehmann, “Chemie derKohlenhydrate: Monosaccharide and Derivate”, Georg Thieme Verlag,Stuttgart 1974.

Suitable hydroxy-protecting groups are especially selected from those ofthe acryl or ester type, e.g. lower alkanoyl, such as formyl, acetyl orisobutyroyl, benzoylformyl, chloroacetyl, dichloroacetyl,trichloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl,phenylacetyl, p-phenylacetyl, diphenylacetyl,2,6-dichloro-4-methylphenox-yacetyl,2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetyl,2,4-bis(1,1-dimethylpropyl)phenoxyacetyl, chlorodiphenyl-acetyl,3-phenylpropionyl, 4-azidobutyroyl, 4-methylthiomethoxybutyroyl,(E)-2-methyl-2-butenoyl, 4-nitro-4-methylpentanoyl, 4-pentenoyl,4-oxopentanoyl, 4,4-(ethylenedithio)-pentanoyl,5-[3-bis(4-methoxyphenyl)-hydroxymethylphenoxy)laevulinyl, pivaloyl,crotonoyl, monosuccinoyl, benzoyl, p-phenylbenzoyl,2,4,6-trimethylbenzoyl, 2-(methylthiomethoxy-me-thyl)benzoyl,2-(chloroacetoxymethyl)benzoyl, 2-[(2-chloroacetoxy)ethyl]be-nzoyl,2-[(2-benzyloxy)ethyl]benzoyl, 2-[2-(4-methoxybenzyloxy)ethyl]benzo-yl,2-iodobenzoyl, o-(di-bromomethyl)benzoyl, o-(methoxycarbonyl)benzoyl,2-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, alkoxycarbonyl, such asmethoxycarbonyl, ethoxycarbonyl, isobutoxycarbonyl,methoxymethylcarbonyl, 9-fluorenylmethoxycarbonyl,2,2,2-trichloroethoxycarbonyl,1,1-dimethyl-2,2,2-trichloroethoxycarbonyl-,2-(trimethylsilyl)ethoxycarbonyl, 2-(phenylsulfonyl)-ethoxycarbonyl,2-(triphenylphosphonio)ethoxycarbonyl, vinyloxycarbonyl,allyloxycarbonyl, p-nitrophenoxycarbonyl, benzyloxycarbonyl,p-methoxybenzyloxycarbonyl, 3,4-dimethoxy-benzyloxycarbonyl,o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl,dansylethoxy-carbonyl, 2-(4-nitrophenyl)ethoxycarbonyl,2-(2,4-dinitrophenyl)ethoxycarbonyl, 2-cyano-1-phenylethoxycarbonyl,S-benzylthlocarbonyl, 4-ethoxy-1-naphthyloxycarbonyl,3′,5′-di-methoxybenzoinyloxycarbonyl, 2-methylthiomethoxyethoxycarbonyl,N-phenylcarbamoyl, dimethylethylphosphinothiolyl, methyldithiocarbonyl;N,N,N′,N′-tetr′amethylphosphoro-diamidoyl, sulfonyl, methanesulfonyl,benzenesulfonyl, toluenesulfonyl, 2-[(4-nitrophenyl)-ethyl]sulfonyl,allylsulfonyl, 2-formylbenzenesulfonyl, nitroxy, or protecting groups ofthe ether type, such as methyl, substituted methyl, preferably loweralkoxymethyl, especially methoxymethyl (MOM), methylthiomethyl,(phenyldimethylsilyl)methoxymethyl, benzyloxy-methyl,p-methoxybenzyloxymethyl, p-nitrobenzyloxymethyl, guaiacolmethyl,tert-butoxy-methyl, 4-pentenyloxymethyl, silyloxymethyl, loweralkoxy-lower alkoxymethyl, especially 2-methoxyethoxymethyl (MEM),2,2,2-trichloroethoxymethyl, 2-(trimethylsilyl)-ethoxymethyl ormenthoxymethyl, tetrahydropyranyl, 3-bromotetrahydropyranyl,tetrahydrothiopyranyl, 4-methoxythiopyranyl, 1-methoxycyclohexyl,4-methoxytetrahydrothiopyranyl,S,S-dioxy-4-methoxytetrahydrothiopyranyl,1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl,1-(2-fluorophenyl)-4-methoxypiperidin-4-yl, 1,4-dioxan-2-yl,tetrahydrofuranyl, tetrahydrothio-furanyl,2,3,3a,4,5,6,7,7a-octahydro-7,-8,8-trimethyl-4,7-methanobenzofuran-2-yl;substituted ethyl, such as 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl,1-[2-(trimethylsilyl)ethoxy]ethyl-, 1-methyl-1-methyl-i-benzyloxyethyl,1-methyl-1-benzyloxy-2-fluoroethyl-1,1-methyl-1-phenoxyethyl,2,2,2-trichloroethyl, 1,1-dianisyl-2,2,2-trich-loroethyl,1,1,1,3,3,3-hexafluoro-2-phenylisopropyl, 2-trimethylsilylethyl,2-(benzylthio)ethyl, 2-(phenylselenyl)ethyl, tert-butyl; allyl orpropargyl, substituted phenyl ethers, such as p-chlorophenyl,p-methoxyphenyl, p-nitrophenyl, 2,4-dinitrophenyl or2,3,5,6-tetrafluoro-4-(trifluoromethyl)-phenyl, benzyl, substitutedbenzyl, such as p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl,p-nitrobenzyl, p-halobenzyl, e.g. p-bromobenzyl, 2,6-dichlorobenzyl,p-cyano-benzyl, p-phenylbenzyl, 2,6-difluorobenzyl, p-azidobenzyl,4-azido-3-chlorobenzyl, 2-tri-fluoromethylbenzyl orp-(methylsulfinyl)benzyl, 2- or 4-picolyl, 3-methyl-2-picolyl,2-quin-olinylmethyl, 1-pyrenylmethyl, diphenylmethyl,p,p′-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl,a-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl,di(p-methoxy-phenyl)phenylmethyl, tri(p-methoxyphenyl)methyl,4-(4′-bromophenacyloxy)phenyl-diphenylmethyl,4,4′,4′-tris(4,5-dichloroph-thalimidophenyl)methyl),4,4′,4′-tris(laevulinoyl-oxyphenyl)methyl,4,4′,4′-tris(benzoyloxyphenyl)methyl,4,4′-dimethoxy-3″-[N-(imidazolyl-me-thyl)]trityl,4,4′dimethoxy-3″-[N-(imidazolylethyl)carbamoyl]trityl,1,1-bis(4-methoxy-phenyl)-1′-pyrenylmethyl,4-(17-tetrahydrobenzo[a,c,g,f-luorenylmethyl)-4′,4″-dimethoxytrityl,9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl,1,3-benzodithiolan-2-yl, S,S-diox of the silyl ether type, such astri-lower alkylsilyl, e.g. trimethylsilyl, triethylsilyl,triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl,dimethylthexylsilyl, tert-butyldimethylsilyl ordi-tert-butylmethylsilyl, tert-butyldiphenylsilyl, triphenylsilyl,diphenylmethylsilyl, tris(trimethylsilyl)silyl,(2-hydroxystyryl)dimethyl-silyl, (2-hydroxystyryl)-diisopropylsilyl,tert-butylmethoxyphenylsilyl or tert-butoxydiphenylsilyl.

Carboxy-protecting groups are especially ester-forming, enzymaticallyand/or chemically removable protecting groups, preferably enzymaticallyand/or chemically removable protecting groups, such as heptyl,2-N-(morpholino)ethyl, cholinyl, methoxyethoxyethyl or methoxyethyl; orthose which are primarily chemically removable, e.g. alkyl, such aslower alkyl, especially methyl, ethyl, substituted lower alkyl (exceptfor benzyl and substituted benzyl), such as substituted methyl,especially 9-fluorenylmethyl, methoxymethyl, methoxy-ethoxymethyl,methylthiomethyl, 2-(trimethylsilyl)ethoxymethyl, benzyloxymethyl,pivaloyloxy-methyl, phenylacetoxymethyl, triisopropylsilylmethyl,1,3-dithianyl-2-methyl, dicyclopropyl-methyl, acetonyl, phenyl,p-bromophenacyl, a-methylphenacyl, p-methoxyphenacyl, desyl,carbamidomethyl, p-azobenzenecarboxamidomethyl, N-phthalimidomethyl or4-picolyl, 2-substituted ethyl, especially 2-iodo-, 2-bromo- or2-chloro-ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl,2-methylthioethyl,2-(p-nitrophenylsulfenyl)ethyl-1,2-(p-toluenesulfonyl)-ethyl,2-(2′-pyridyl)ethyl, 2-(p-methoxyphenyl)ethyl,2-(diphenylphosphino)ethyl, 1-methyl-1-phenylethyl,2-(4-acetyl-2-nitrophenyl)ethyl or 2-cyanoethyl, tert-butyl,3-methyl-3-pentyl, 2,4-dimethyl-3- or .omega.-chloro-lower alkyl,especially 4-chlorobutyl or 5-chloropentyl, cyclopentyl, cyclohexyl,lower alkenyl, especially allyl, methallyl, 2-methylbut-3-en-2-yl,3-methylbut-2-enyl or 3-buten-1-yl, substituted lower alkenyl,especially 4-(trimethylsilyl)-2-buten-1-yl, cinnamyl ora-methylcinnamyl, lower alkynyl, such as prop-2-ynyl, phenyl,substituted phenyl, especially 2,6-dialkylphenyl, such as2,6-dimethylphenyl, 2,6-diisopropylphenyl,2,6-di-tert-butyl-4-methylphenyl, 2,6-di-tert-butyl-4-methoxyphenyl,p-(methylthio)-phenyl or pentafluorophenyl, benzyl, substituted benzyl,especially triphenylmethyl, diphenyl-methyl, bis(o-nitrophenyl)methyl,9-anthrylmethyl, 2-(9,10-dioxo)anthrylmethyl, 5-dibenzo-suberyl,1-pyrenylmethyl, 2-(trifluoromethyl)-6-chromonylmethyl,2,4,6-trimethylbenzyl, p-bromobenzyl, o-nitrobenzyl, p-nitrobenzyl,p-methoxybenzyl, 2,6-dimethoxybenzyl, 4-(methylsulfinyl)benzyl,4-sulfobenzyl, 4-azidomethoxybenzyl,4-(N-[1-(4,4-dimethyl-2,6-dioxo-cycl-ohexylidene)-3-methylbutyl]amino)benzyl,piperonyl or p-polymer-benzyl, tetrahydro-pyranyl, tetrahydrofuranyl, orsilyl radicals, such as tri-lower alkylsilyl, especially trimethylsilyl,triethylsilyl, tert-butyldimethylsilyl, isopropyldimethylsilyl ordi-tert-butylmethylsilyl, or phenyl-di-lower alkylsilyl, such asphenyldimethylsilyl; alternatively a carboxy group can also be protectedin the form an oxazolyl, 2-alkyl-1,3-oxazolinyl,4-alkyl-5-oxo-1,3-oxazol-idinyl or 2,2-bistrifluo4-alkyl-5-oxo-1,3-oxazolidinyl radical.

Amide-protecting groups are especially allyl, tert-butyl, N-methoxy,N-benzoyloxy, N-methyl-thio, triphenylmethylthio,tert-butyldimethylsilyl, triisopropylsilyl, 4-(methoxymethoxy)phenyl,2-methoxy-1-naphthyl, 9-fluorenyl, tert-butoxycarbonyl,N-benzyloxycarbonyl, N-methoxy- or N-ethoxy-carbonyl, toluenesulfonyl,N-buten-1-yl, 2-methoxycarbonylvinyl, or especially alkyl, such as loweralkyl, or more especially substituted alkyl, especially benzyl, benzylsubstituted by one or more radicals selected from lower alkoxy, such asmethoxy, lower alkanoyloxy, such as acetoxy, lower alkylsulfinyl, suchas methylsulfinyl, dicyclopropylmethyl, methoxymethyl, methylthiomethyland N-benzoyloxymethyl; or bis(trimethylsilyl)methyl,trichloroethoxymethyl, tert-butyldimethylsilyloxymethyl,pivaloyloxymethyl, cyanomethyl, benzyl, 4-methoxybenzyl,2,4-dimethoxybenzyl, 3,4-dimethoxybenzyl, 2-acetoxy-4-methoxy-benzyl,o-nitrobenzyl, bis(4-5 methoxyphenyl)phenylmeth-yl,bis(4-methylsulfinylphenyl)methyl, pyrrolidinomethyl, diethoxymethyl,1-methoxy-2,2-dimethylpropyl or 2-(4-methylsulfonyl)ethyl.

It is characteristic of protecting groups that they are simple to remove(that is to say without undesirable secondary reactions taking place),for example by solvolysis, reduction, photolysis or alternatively underconditions analogous to physiological conditions, for exampleenzymatically. Typically, the protecting and activating steps areperformed simultaneously.

The process of the present invention will now be further described inthe following examples for the synthesis of 5-CNAC:

EXAMPLES Example 1 Preparation of6-chloro-2H-1,3-benzoxazine-2,4(3H)-dione

5-chlorosalicylamide (300 g, 1.75 mol) and water (900 ml) were placed ina 3 liter, 4-neck round-bottomed flask under a nitrogen atmosphere andstirred. 5-ethyl-2-methyl-pyridine (284 g, 2.27 mol) and n-butyl acetate(900 ml) were added to the mixture. The mixture was cooled to 0-5° C.(jacket-10° C.) and dropwise addition of ethyl chloroformate (233 g,2.10 mol) was started. This addition continued over a period ofapproximately one hour. When the addition was completed, the reactionmixture was slowly heated (in about two hours) to reflux and kept underreflux for an additional period of about 5 hours (jacket 110° C.,internal temperature (IT) 90° C.). The resulting slurry was allowed tocool to room temperature, and hydrochloric acid (28 ml, 37% m/m, 0.34mol) was added and the mixture stirred for about 30 minutes. Theresulting slurry was vacuum filtered, the filter cake was washed withn-butyl acetate followed by water (600 ml) and was allowed to dryovernight in vacuo at 60° C. 321 g (93%) of6-chloro-2H-1,3-benzoxazine-2,4(3H)-dione (6-chloro carsalam) wasisolated after drying.

Example 2 Preparation of N-5-(chlorosalicyloyl)-8-aminocaprylic acid(5-CNAC)

6-chloro-2H-1,3-benzoxazine-2,4(3H)dione (180.5 g, 0.91 mol), sodiumbromide (18.7 g, 0.18 mol) and dimethylformamide (840 ml) were placed ina 3 liter, 4-neck round bottomed flask under a nitrogen atmosphere andstirred. Ethyl-8-chloro-octanoate (188.3 g, 0.911 mol) was added in oneportion, and rinsed with dimethylformamide (60 ml). The mixture washeated up to 100-105° C. jacket 120° C.) and anhydrous sodium carbonate(51.7 g, 0.47 mol) was added portion wise over a period of 2 hours.After the reaction was complete, the solvent was distilled off underreduced pressure (60-20 mbar, internal temperature 75-120° C., jacket100-130° C.) to leave an oily residue. Water (700 ml) was added at85-95° C. over 10-20 minutes, followed by sodium hydroxide (380 ml, 30%w/w), followed by a rinse with 20 ml of water. The mixture was stirredfor two hours at 85-100° C., then sulfuric acid (60 ml 50% w/w) wasadded at 60-65° C. until the pH of the mixture was between 8 and 9 thenethyl acetate (700 ml) was added at 60-65° C. over 30 to 60 minutes.Then more sulfuric acid (221 ml, 50% w/w) was added at 60-65° C. over aperiod of one hour until the pH of the mixture was between 2 and 3.5.Afterwards the two phases were allowed to separate. The aqueous phasewas discarded, and the remaining organic phase washed with water(300-360 ml) at 60-65° C. Then water (600 ml) and sodium hydroxide (10.8g, 30% w/w and 40 ml of water), followed by a rinse of 20 ml of water,were added (in order to remove small about ofN,O-5-(chlorosalicyloyl)-di-octanoic acid by-product), and the organicsolvent distilled off under atmospheric pressure (jacket 110-120° C.,IT: 80-100° C.). To the resulting suspension, ethanol (1500 ml) wasadded at 50-65° C. The clear solution was allowed to cool down to 40-45°C. and seed crystals (0.12 g) were added and the solution stirred for 20to 30 minutes until crystallisation was set on. Cooling was continueddown to 0-5° C. in a period of 1-2 hours. The solid was collected byvacuum filtration and washed with ethanol/water 7:3 (540 ml), and driedunder vacuum (10-50 mbar) at 60° C. overnight to yield 237 g ofN-5-(chlorosalicyloyl)-8-aminocaprylic acid (84%).

Example 3 Preparation of the di-sodium salt, monohydrate ofN-5-(chlorosalicyloyl)-8-aminocaprylic acid

N-5-(chlorosalicyloyl)-8-aminocaprylic acid (3.5 kg, 11.15 mol), acetone(9450 ml) and water (875 ml, purified) were placed in a 50 liter vesselunder a nitrogen atmosphere and stirred at 45-55° C. (jacket 60° C.)until a clear solution was formed (20 to 30 minutes). Sodium hydroxide(297 g, 30% w/w, 22.3 mol) was added in such a way as to maintain thetemperature at 45-55° C., followed by a solution of acetone/water 3:1v/v (1050 ml). The hot (50° C.) solution was passed then over apolishing filter and the filtrate transferred to another clean vesseland heated to 45 to 55° C. The transfer line was rinsed with hot (45-55°C.) acetone/water 3:1 v/v (1050 ml), and then acetone (about 10.5 liter)was added in such a way to keep the temperature around 45-55° C. (jacket55° C.). Then, the temperature was lowered to 45-48° C. and seedcrystals (4 g) were added. The mixture was stirred for about 20-30minutes to obtain a fine suspension and induce crystallization, thenmore acetone (28 I) was added over one hour in such a way to maintain atemperature of 45-50° C. (jacket 55° C.). Afterwards, a slow stirringwas prolonged for one hour at 45-50° C., then the temperature waslowered to 0-5° C. over a period of two hours. Stirring was continued at0-5° C. for an hour, then crystals were collected by centrifugation,washed with cold acetone/water 95:5 v/v (7 I) and dried under vacuum50-60 mbar at 50-55° C. for at least 24 hours to yield 4.19 kg of 5-CNACdi-sodium monohydrate (95% yield).

The invention claimed is:
 1. In a method of preparing an N-substitutedsalicylamide, wherein the N-substituted salicylamide is achieved byreaction of a carsalam derivative with ethyl-8-bromooctoanoate, theimprovement comprising: reacting the carsalam derivative with achloro-substituted compound of formula (III)

wherein n is an integer from 1 to 8, Q represents a group readilyconvertible to a carboxylic acid moiety and R⁵ and R⁶ are independentlyselected from hydrogen, —OH, NR³R⁴, halogen, C₁, C₂, C₃ or C₄ alkyl, C₁,C₂, C₃ or C₄ alkoxy, C₂, C₃ or C₄ alkenyl where R³ and R⁴ are eachindependently selected from hydrogen, —OH, C₁, C₂, C₃ or C₄ alkyl, C₁,C₂, C₃ or C₄ haloalkyl, C₁, C₂, C₃ or C₄ alkoxy, C₂, C₃ or C₄alkenyl,wherein said reacting step is carried out by mixing in an inertatmosphere and in the presence of an aprotic solvent, the carsalamderivative with 1 equivalent of the chloro-substituted compound offormula III and 0.2 equivalents an alkali metal-bromide, heating to100-105° C., followed by slow addition of 0.55 equivalents of an alkalimetal hydroxide base or an alkali metal carbonate base.
 2. A methodaccording to claim 1 wherein the alkali metal-bromide enables theformation in situ of a compound of formula (IIIb)


3. A method according to claim 1 wherein the compound of formula (III)is a compound of formula (III.II):

wherein R¹ represents a protecting group for the carboxylic moiety.
 4. Amethod according to claim 3 wherein R¹ is selected from a linear orbranched alkyl group containing 1, 2, 3, 4, 5 or 6 carbon atoms.
 5. Amethod according to claim 4 wherein R¹ is ethyl.
 6. A method accordingto claim 1 wherein n is
 6. 7. A method according to claim 1 wherein eachR⁵ and R⁶ represents H.
 8. A method according to claim 1 wherein n is 6and each CR⁵R⁶ is CH₂.
 9. In a method of preparing a compound of thegeneral formula IV:

where R⁵, R⁶, Q and n are as defined in claim 1, t is 0,1,2,3,4,5 or 6,m is 1,2,3 or 4 and R², or where m>1 each R² independently, is selectedfrom —OH, NR³R⁴, halogen, C₁, C₂, C₃ or C₄ alkyl, C₁, C₂, C₃ or C₄haloalkyl, C₁, C₂, C₃ or C₄ alkoxy, C₂, C₃ or C₄ alkenyl and R³ and R⁴are each independently selected from hydrogen, —OH, C₁, C₂, C₃ or C₄alkyl, C₁, C₂, C₃ or C₄ haloalkyl, C₁, C₂, C₃ or C₄ alkoxy, C₂, C₃ or C₄alkenyl wherein the compound of formula IV is achieved by reaction of acarsalam derivative with ethyl-8-bromooctoanoate, the improvementcomprising: (i) reacting a compound of formula (I)

with a chloroformate in the presence of a weak organic base to form acompound of formula (II)

and (ii) reacting in an inert atmosphere and in the presence of anaprotic solvent, the compound of formula II with one equivalent of acompound of formula (III),

and 0.2 equivalents of an alkali metal-bromide, heating to about 100°C., followed by slow addition of 0.55 equivalents of an alkali metalhydroxide base or an alkali metal carbonate base to provide a compoundof formula (IV).
 10. A method according to claim 9 wherein the compoundof formula (IV) is subjected to a subsequent saponification step.
 11. Amethod according to claim 10 wherein the saponification step is carriedout without prior isolation of the compound of formula (IV).
 12. Amethod according to claim 9 wherein the compound of formula (IV) isformed in mixture with a compound of formula (VI)

where R², m, t, n and Q are as defined in claim
 9. 13. A methodaccording to claim 12 wherein the compounds of formulae (IV) and (VI)are subjected to a subsequent saponification step.
 14. A method inaccording to claim 13 wherein the saponification step is carried outwithout prior isolation of the compounds of formulae (IV) and (VI). 15.A method according to claim 9 wherein compound (III) is a compound ofthe formula (III.II )

where R¹ is a protecting group for the carboxy moiety, whereby thecompound of formula (IV) is a compound of the formula (IV.I):


16. A method according to claim 14 including the further step ofremoving the group R¹ to form a compound of the formula (IV.II):


17. A method according to claim 14 wherein the compound of formula(IV.I) is formed in mixture with a compound of formula (VI.I)

where R2, m, t, n and Q are as defined in claim
 9. 18. A methodaccording to claim 16 including the further step of reacting thecompounds of formulae (IV.I) and (VI.I) each to form a the compound offormula (IV.II).
 19. A method according to claim 17 wherein said furtherstep is performed without prior isolation of the compounds of formulae(IV.I) and (VI.I).
 20. A method according to claim 17 wherein saidfurther step comprises a saponification step.
 21. A method according toclaim 14 wherein R¹ is linear or branched alkyl containing 1, 2, 3, 4, 5or 6 carbon atoms.
 22. A method according to claim 20 wherein R¹ isethyl.
 23. A method according to claim 15, further comprising theadditional step of reacting the compound of formula (IV.II) with M_(a)Yto provide the compound of formula (V):

where M_(a) is an alkali metal and Y is a basic counter ion.
 24. Amethod according to claim 23, wherein the metal M_(a) is Na.
 25. Amethod according to claim 23, wherein Y is OH.
 26. A method according toclaim 23 wherein the compound (V) is a hydrate.
 27. A method accordingto claim 23 wherein M_(a)Y is NaOH.
 28. A method according to claim 9wherein m is
 1. 29. A method according to claim 9 wherein R² is chloro.30. A method according to claim 27 wherein R² is at the 5-position. 31.A method according to claim 9 wherein every R⁵ and every R⁶ is hydrogen.32. A method according to claim 9 wherein n is
 6. 33. A method accordingto claim 9 wherein n is 6 and each CR⁵R⁶ is CH₂.
 34. A method accordingto claim 15 wherein the compound of formula (IV.II) isN-(5-chlorosalicyloyl)-8-aminocaprylic acid.
 35. A method according toclaim 1, wherein the alkali metal bromide is NaBr.
 36. A methodaccording to claim 9 wherein the weak organic base is substantiallywater insoluble.
 37. A method according to claim 9 wherein the weakorganic base is an alkyl-substituted pyridine.
 38. A method according toany claim 36 wherein the weak organic base is 5-ethyl-2-methyl-pyridine.39. A method according to claim 9 wherein the chloroformate isethylchloroformate.
 40. A method according to claim 9 wherein step (i)is performed in the presence of an alkyl acetate.
 41. A method accordingto claim 9, wherein step (i) is performed in a two phase system, thephases comprising respectively water and an organic solvent.
 42. Amethod according to claim 41 wherein the organic solvent is an alkylacetate.
 43. A method according to claim 41 wherein the alkyl acetate isbutyl acetate.
 44. A method according to claim 23, wherein theadditional step is performed in an acetone/water mix.
 45. A methodaccording to claim 44 wherein the acetone:water ratio is about 3:1. 46.A method according to claim 9 wherein the compound of formula (IV)contains less than 2.2% di-acid by-product.
 47. A method according toclaim 15 wherein the compound of formula (IV.II) contains less than 2.2%di-acid by-product.
 48. A method according to claim 23 wherein thecompound of formula (V) contains less than 2.2% di-acid by-product. 49.A method according to claim 16 wherein the compound of formula (IV.II)is the compound:


50. A method according to claim 23 wherein the compound of formula V isthe compound:


51. A method according to claim 16 further comprising formulating acompound of formula (IV.II), into pharmaceutical formulation, thepharmaceutical formulation additionally having at least one activeingredient.
 52. A method according to claim 49 further comprisingformulating a compound of formula (IVA), into pharmaceuticalformulation, the pharmaceutical formulation additionally having at leastone active ingredient.
 53. A method according to claim 23 furthercomprising formulating a compound of formula (V), into pharmaceuticalformulation, the pharmaceutical formulation additionally having at leastone active ingredient.
 54. A method according to claim 50 furthercomprising formulating a compound of formula (VA), into pharmaceuticalformulation, the pharmaceutical formulation additionally having at leastone active ingredient.
 55. A method according to claim 1 wherein thereaction mixture is heated to about 100° C.
 56. A method according toclaim 9 wherein the reaction mixture is heated to about 100° C.